We propose to study the hypothesis that susceptiblity to disease in man is governed by an immune response (IR) gene. There is evidence that defective IR genes are linked to HLA antigens. The definite association of ankylosing spondylitis (AS) and related diseases with HLA-B27 and probable association of multiple sclerosis (MS) with antigens HLA-A3, HLA-B7, HLA-DW2, and MS-B (a B lymphocyte specificity) indicate that the HLA chromosome region can be used as a genetic marker to investigate the origins and etiology of disease. New work with B lymphocyte specificities, possibly analogous to Ia in mice, appears to show that these antigens have an even stronger linkage with disease susceptibility than the other HLA loci. By initially studying primarily AS and MS to try to identify the HLA complexes and racial origins of the patients with the original mutations, we hope insight may be gained into the genetics of susceptibility, racial differences in susceptibility, the role of IR genes in susceptibility, and the effectiveness of HLA as a genetic marker in identifying defective IR genes in different diseases. Family studies, computer derivation of "diseased" chromosome frequencies, and linkage analysis will be used to evaluate antigen data.